tbuckley/cabot-search huggingface dataset:
Abstract 2010: Transcriptional antagonism by CDK8 inhibition improves therapeutic efficacy of MEK inhibitors
Authors: Clare F. Malone, Minjee Kim, Gabriela Alexe, Alexandra B. Forman, Amanda Robichaud, Amy Saur Conway, Amy Goodale, John M. Hatcher, Nathanael S. Gray, Federica Piccioni, Kimberly Stegmaier
Journal: Cancer Research (2022)

Abstract Mutations in the RAS/MAPK pathway are frequent drivers of oncogenesis. Clinically approved MEK inhibitors are effectively used to target RAS-pathway driven cancers in combination with RAF inhibitors in BRAF mutant cancers such as melanoma and non-small cell lung cancer. However, single agent treatment with MEK inhibitors is not typically sufficient for clinical benefit. Therefore, combination therapy approaches will be required for maximal efficacy in most advanced cancers. Here, we sought to identify MEK inhibitor-based combination therapy approaches in the setting of RAS-mutant neuroblastoma. Neuroblastoma is a cancer that arises in the developing peripheral nervous system. Children with low-risk disease frequently benefit from therapy, but 50-60% of children with high-risk disease will ultimately relapse, and relapsed disease is generally incurable. We performed genome-scale functional genomic drug modifier screens and identified mediator kinase module members CCNC and CDK8 as two genes that when lost sensitize RAS-mutant NBL to MEK inhibition. We used small molecule inhibitors of CDK8 and found that combined inhibition of MEK and CDK8 leads to an improved therapeutic response in vitro and in vivo in a xenograft model of neuroblastoma. Using transcriptional profiling, we established that CDK8 loss and MEK inhibition induce opposite transcriptional signatures. When combined, CDK8 loss prevents the compensatory upregulation of the pro-growth gene expression program induced by MEK inhibition, while the downregulation of MAPK signaling is maintained. Finally, we show that this combination is effective in a subset of other RAS-mutant cancers including pancreatic and lung cancers. Together these data suggest that the mediator kinase module is critical for the adaptive pro-survival transcriptional response induced by MEK inhibition in RAS-mutant neuroblastoma and other RAS-driven malignancies, and that the addition of a CDK8 inhibitor may improve clinical response to MEK inhibitors. Our data supports a model where agents with antagonistic transcriptional programs can have synergistic therapeutic effects when combined, which may be a broadly relevant approach in combination therapies. Citation Format: Clare F. Malone, Minjee Kim, Gabriela Alexe, Alexandra B. Forman, Amanda Robichaud, Amy Saur Conway, Amy Goodale, John M. Hatcher, Nathanael S. Gray, Federica Piccioni, Kimberly Stegmaier. Transcriptional antagonism by CDK8 inhibition improves therapeutic efficacy of MEK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2010.
Abstract 5684: Protein homeostasis modulation is critical for cancer cell survival upon chaperone mediated proteotoxic stress
Authors: Sara Sannino, Jeffrey L. Brodsky
Journal: Cancer Research (2022)

Abstract Cancer cells survive under extreme environments that alter protein homeostasis, thereby provoking cellular stress responses, such as the unfolded protein response (UPR) and the integrated stress response (ISR). These pathways increase the expression of molecular chaperones to prevent the accumulation of toxic proteins in the cell. One molecular chaperone in particular, Hsp70, plays a central role in both cellular protection and the response to proteotoxic insults. This is perhaps most evident in cancer cells, some of which overexpress Hsp70 and thrive even when harboring high levels of misfolded, aggregated, and/or unassembled protein complexes. In an effort to define how cells compensate for compromised proteostasis, we examined the adaptive response in breast cancer cells after challenge with a specific Hsp70 inhibitor. We first showed that established breast cancer cell lines bin into classes based on their sensitivity to the drug. We next discovered that resistant cells have higher autophagy levels compared to the more sensitive lines. Moreover, gene and protein expression studies and imaging methods showed that autophagy was further induced by Hsp70 inhibition in resistant breast cancer cells. Consistent with the fact that Hsp70 normally targets aberrant proteins for degradation, our data indicated that resistance to compromised Hsp70 activity arose from elevated levels of autophagy. We next showed that Hsp70 inhibition specifically triggers the ISR pathway. Unexpectedly, protection against the Hsp70 inhibitor was dependent on the ISR sensor, GCN2, which is most commonly associated with the amino acid starvation response. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating the PERK pathway. These data reveal an unexpected route through which cancer cells can adapt to chaperone targeted-proteotoxicity and position GCN2 and autophagy as critical compensatory mechanisms for cancer cells when proteostasis is compromised. Citation Format: Sara Sannino, Jeffrey L. Brodsky. Protein homeostasis modulation is critical for cancer cell survival upon chaperone mediated proteotoxic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5684.
Abstract SY11-02: Long-read sequencing reveals complex patterns of wraparound transcription in polyomaviruses
Authors: James A. DeCaprio, Jason Nomburg, Matthew Meyerson
Journal: Cancer Research (2022)

Abstract Polyomaviruses (PyV) are ubiquitous pathogens that can cause devastating human diseases. Due to the small size of their genomes, PyV utilize complex patterns of RNA splicing to maximize their coding capacity. Despite the importance of PyV to human disease, their transcriptome architecture is poorly characterized. Here, we compare short- and long-read RNA sequencing data from eight human and non-human PyV. We provide a detailed transcriptome atlas for BK polyomavirus (BKPyV), an important human pathogen, and the prototype PyV, simian virus 40 (SV40). We identify pervasive wraparound transcription in PyV, wherein transcription runs through the polyA site and circles the genome multiple times. Comparative analyses identify novel, conserved transcripts that increase PyV coding capacity. One of these conserved transcripts encodes superT, a T antigen containing two RB-binding LxCxE motifs. We find that superT-encoding transcripts are abundant in PyV-associated human cancers. Together, we show that comparative transcriptomic approaches can greatly expand known transcript and coding capacity in one of the simplest and most well-studied viral families. Citation Format: James A. DeCaprio, Jason Nomburg, Matthew Meyerson. Long-read sequencing reveals complex patterns of wraparound transcription in polyomaviruses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY11-02.
Abstract 1386: MAPK inhibition remodels antigen presentation in pancreatic ductal adenocarcinoma
Authors: Amanda L. Creech, Thuc M. Le, Evan R. Abt, Joseph R. Capri, Timothy R. Donahue, Caius G. Radu
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival rate of less than 10%, highlighting the need for new therapeutic options. Hallmarks of this aggressive disease include constitutive activation of the MAPK signaling pathway via mutant KRAS (mKRAS) and an immunosuppressive tumor microenvironment (TME). Constituently-active KRAS has now been rendered targetable via clinical-stage mKRAS-specific small molecule inhibitors. While the impact of KRAS inhibition on tumor growth is well-studied, its ability to engender anti-tumor adaptive immune responses is not fully understood. Prior data generated by our group demonstrated mKRAS inhibition (mKRASi) increased expression of genes associated with antigen presentation in two models of PDAC in vitro. Additionally, proteomic analysis revealed increased expression of two tumor associated antigens (TAAs), MSLN and PSCA. To better understand the alteration of antigen presentation in response to MAPK signaling perturbation, we measured surface expression of MHC-I and PD-L1 after mKRAS and/or SHP2 inhibition via flow cytometry in a PDAC-KRASG12C model in vitro. Results demonstrate an additive increase in MHC-I surface expression following inhibition of SHP2 and in combination with mKRASi that is more pronounced in the setting of type I interferon (IFN). Inhibition of MEK in a PDAC KRASG12D model recapitulates these findings. Addition of a JAK inhibitor did not suppress the additional MHC-I expression suggesting a potential JAK/STAT-independent mechanism for this observation. To better understand the extent of alteration of presented epitopes in response to these perturbations we established an immunopeptidomics profiling workflow, using LC-MS/MS to identify peptide ligands eluted from MHC-I complexes after inhibition of mKRAS and/or SHP2. We additionally profiled epitope alterations after the addition of type I or II IFN. MAPK perturbation resulted in more unique epitopes identified, especially with dual inhibition of mKRAS and SHP2 and further potentiated by type I IFN. Furthermore, we were able to directly identify epitopes derived from MSLN and PSCA in our cell line models. This data demonstrates the potential for MAPK inhibition to render PDAC more sensitive to the adaptive immune system and synergize with immunotherapeutic treatment strategies. Additionally, direct identification of epitopes presented by cancer cells via mass spectrometry can aid in the rational design of targeted immunotherapies. Citation Format: Amanda L. Creech, Thuc M. Le, Evan R. Abt, Joseph R. Capri, Timothy R. Donahue, Caius G. Radu. MAPK inhibition remodels antigen presentation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1386.
Myocardial brain-derived neurotrophic factor regulates cardiac bioenergetics through the transcription factor Yin Yang 1
Authors: Xue Yang, Manling Zhang, Bingxian Xie, Zishan Peng, Janet R Manning, Raymond Zimmerman, Qin Wang, An-chi Wei, Moustafa Khalifa, Michael Reynolds, Jenny Jin, Matthew Om, Guangshuo Zhu, Djahida Bedja, Hong Jiang, Michael Jurczak, Sruti Shiva, Iain Scott, Brian O’Rourke, David A Kass, Nazareno Paolocci, Ning Feng
Journal: Cardiovascular Research (2022)

Abstract Aims Brain-derived neurotrophic factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, tropomyosin-related kinase receptor (TrkB), are expressed in cardiomyocytes; however, the role of myocardial BDNF signalling in cardiac pathophysiology is poorly understood. Here, we investigated the role of BDNF/TrkB signalling in cardiac stress response to exercise and pathological stress. Methods and results We found that myocardial BDNF expression was increased in mice with swimming exercise but decreased in a mouse heart failure model and human failing hearts. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). In response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The downregulation of PGC-1α in cTrkB KO mice exposed to exercise or TAC resulted in decreased cardiac energetics. We further unravelled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signalling pathway, the pleiotropic transcription factor Yin Yang 1. Conclusion Taken together, our findings suggest that myocardial BDNF plays a critical role in regulating cellular energetics in the cardiac stress response.
Abstract 3980: Targeting Ewing sarcoma based on RNA expression
Authors: Kaitlyn Smith, Divya Gandra, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Giselle S. Sholler, Javier Oesterheld, Erin Trovillion
Journal: Cancer Research (2022)

Abstract Purpose: Ewing sarcoma (ES) is the second most common malignant bone sarcoma in children and young adults. Current treatment for Ewing sarcoma includes a combination of cytotoxic chemotherapeutic agents and local control with radiation and/or surgery. The survival rate of those with Ewing sarcoma has seen very little improvement over the past several decades and remains dismal for those with recurrent or metastatic disease. The purpose of this study is to identify novel agents currently available for use in Ewing sarcoma. Methods: Novel targeted approaches for the treatment of ES were identified using RNA sequencing performed on 15 ES patient derived cell lines with bioinformatic analysis of gene expression. Targeted agents were tested on patient cell lines at escalating doses. At 48 hours cell viability was assessed with CellTiter-Glo 2.0 and analyzed with GraphPad Prism to determine the IC50. At 24- and 48-hours western blot analysis was performed to evaluate the effect on cell cycle and apoptosis. Combination studies with standard chemotherapy were performed to evaluate for synergy using SynergyFinder 2.0. Results: RNA analysis identified HDAC2, ALK and JAK1 as a potential therapeutic targets. The pan-HDAC inhibitor, Panobinostat, was cytotoxic to all Ewing sarcoma cell lines tested with clinically relevant IC50s (≤200nM) and repressed expression of Cyclin D1 and pRB. ALK inhibition was cytotoxic at doses slightly higher than that of clinical relevance. HDAC and ALK expression levels correlated to cell sensitivity. JAK1 inhibition does not appear to have efficacy at clinically relevant dosing. Panobinostat synergizes with Doxorubicin at clinically relevant doses. Conclusion: This work highlights that RNA expression may identify potential targets which could be effective in treating Ewing sarcoma or potentially improve the efficacy of standard of care drugs. HDAC and ALK inhibition show a decrease in cell viability in ES cell line models. Future studies of HDAC and ALK inhibitors will aim to determine efficacy in xenograft models. Citation Format: Kaitlyn Smith, Divya Gandra, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Giselle S. Sholler, Javier Oesterheld, Erin Trovillion. Targeting Ewing sarcoma based on RNA expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3980.
Abstract 945: Gab2 deficiency protects against Flt3-ITD driven acute myeloid leukemia <i>in vivo</i>
Authors: Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schönberger, Nina Cabezas-Wallscheid, Melanie Börries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Journal: Cancer Research (2022)

Abstract Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) frequently co-exist with inactivating DNMT3A mutations and predict poor prognosis in acute myeloid leukemia (AML). In vitro studies implicated the docking protein Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. By utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice survived significantly longer, had reduced blast counts and exhibited an attenuated spleen and liver pathology as compared to their Gab2-proficient littermates. Further, leukemic bone marrow isolated from Gab2 deficient mice displayed a reduced colony forming unit capacity and an increased sensitivity towards the Flt3 inhibitor quizartinib. Using RNA sequencing, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors as it induces their expression and additionally serves as a downstream effector. Consequently, Gab2 promotes AML aggressiveness as well as drug resistance by incorporating the receptor tyrosine kinases Axl and Ret into the Flt3-ITD signaling network. Therefore, our data identify GAB2 as a promising biomarker as well as a therapeutic target in human AML. Citation Format: Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schönberger, Nina Cabezas-Wallscheid, Melanie Börries, Sebastian Halbach, Anna L. Illert, Tilman Brummer. Gab2 deficiency protects against Flt3-ITD driven acute myeloid leukemia in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 945.
IgG4-Related Ophthalmic Disease
Authors: Yi-Min Huang, Pei-Hsuan Lin
Journal: New England Journal of Medicine (2022)

A 67-year-old man presented to the ophthalmology clinic with swollen eyelids and proptosis. Biopsy of the right lacrimal gland showed a lymphoplasmacytic infiltrate with IgG4-positive plasma cells.
Abstract 3873: Profiling the tumor microenvironment within clear cell renal cell carcinoma by single-nuclei RNA-Seq
Authors: Ruiyang Liu, Ilya Strunilin, Yige Wu, Alla Karpova, Siqi Chen, Chia-Kuei Mo, Yize Li, Feng Chen, Li Ding
Journal: Cancer Research (2022)

Abstract Clear cell renal carcinoma (ccRCC) appears as one of the most immune infiltrated tumors in pan-cancer comparisons. A systematic characterization of the immune microenvironment of ccRCC is important for understanding the disease progression and would be beneficial to predicting disease outcomes. To better understand the cellular components within the tumor microenvironment (TME), the interactions among different cell types, and the contribution to disease outcomes, we collected 34 ccRCC tumor samples for single-nuclei RNA-Seq (snRNASeq) profiling. We obtained 161312 cells in total, including 6791 stroma cells (endothelial cells, fibroblasts and myofibroblasts) and 38918 immune cells (lymphoid and myeloid populations).Analysis of cell-cell-interactions suggests tumor cells interact most frequently with stroma and immune cells. Of interest, we noticed some ligand-receptor pair interactions commonly found among all samples, such as VEGFA from tumor cells with VEGFR1/2 from endothelial cells, suggesting the presence of angiogenesis. Within endothelial populations, we found a common interaction between ANGPT2 and TEK, whose interaction scores are moderately correlated with lymphocyte percentages across samples, suggesting this interaction could contribute to endothelium leakage and lymphocytes recruitment. To better understand the immune cell subtype/states within each immune cell type, we further distinguished 14 different subpopulations within macrophages according to key marker expressions. The presence of the subpopulations suggest diverse states and heterogeneous functions within macrophages. Of note, the expression of iron uptake receptor TFRC is elevated in higher-grade tumors. Higher TFRC expression is associated with poorer prognosis, which is also validated by the CPTAC discovery cohort using bulk proteomics data. In summary, our study showcases the potential of using snRNA-Seq to profile the TME of ccRCC, in identifying important cell-cell interactions and predicting disease outcomes. Citation Format: Ruiyang Liu, Ilya Strunilin, Yige Wu, Alla Karpova, Siqi Chen, Chia-Kuei Mo, Yize Li, Feng Chen, Li Ding. Profiling the tumor microenvironment within clear cell renal cell carcinoma by single-nuclei RNA-Seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3873.
Abstract 6026: A novel humanized mouse model based on NOG-FcgR-/-mice recapitulates anti-tumor immune reactions by human immune systems in response to anti-PD-1 antibody (Nivolumab)
Authors: Ikumi Katano, Asami Hanazawa, Iyo Otsuka, Takuya Yamaguchi, Misa Mochiduki, Kenji Kawai, Ryoji Ito, Motohito Goto, Takahiro Kagawa, Takeshi Takahashi
Journal: Cancer Research (2022)

Abstract Humanized mice with human hematopoietic and immune systems have been frequently used for examining in vivo anti-cancer effects of various drugs, including immune checkpoint inhibitors (ICIs) like anti-PD-1 or anti-CTLA-4 antibodies, yet the reliability of the mouse models to be improved. We have recently developed NOD-scid, IL-2Rγ KO (NOG) mice deficient for the mouse FcεRI and FcγIIb genes, thus lacking the expression of functional mouse FcγRs, (NOG-FcγR-/-) and the activity of endogenous antibody-dependent cellular cytotoxicity (ADCC). Reconstitution experiments with human hematopoietic stem cells (HSC) showed that NOG-FcγR-/- mice had higher engraftment capacity for human leucocytes than NOG mice, namely the numbers of HSC-derived human CD19+ B cells and CD33+ myeloid cells, but not CD3+ T cells, were higher in the various tissues in NOG-FcγR-/- mice than those in NOG mice. In tumor-bearing experiments using those reconstituted mice, it was of interest that humanized NOG-FcγR-/- mice (huNOG-FcγR-/-) could invoke strong tumor growth suppression or rejection in response to anti-PD-1 antibody (Nivolumab) treatment in several cancer cell lines, which was absent in conventional huNOG mice. Accordingly, Nivolumab treatment in huNOG-FcγR-/- mice induced a significant increase of human T cells in number in the spleen and infiltration of human T cells with Granzyme B and Perforin-expression into tumor. Furthermore, the composition of activated T cells was different between huNOG-FcγR-/- and huNOG mice. HuNOG-FcγR-/- mice had elevated numbers of activated T cells, both T central memory cells (TCM) and T effector memory cells (TEM), whereas huNOG mice showed an opposite trend, reduced TCM and TEM and increase of naïve T cells. Our results suggest that the novel NOG-FcγR-/- mice become a good model for elucidating the cellular and molecular mechanisms of human tumor rejection by human T cells, and that they will provide a superior in vivo platform for evaluation of anti-cancer drugs, especially, in combination with ICIs like Nivolumab. Citation Format: Ikumi Katano, Asami Hanazawa, Iyo Otsuka, Takuya Yamaguchi, Misa Mochiduki, Kenji Kawai, Ryoji Ito, Motohito Goto, Takahiro Kagawa, Takeshi Takahashi. A novel humanized mouse model based on NOG-FcgR-/-mice recapitulates anti-tumor immune reactions by human immune systems in response to anti-PD-1 antibody (Nivolumab) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6026.